Oncogenic Signaling Pathways in The Cancer Genome Atlas.

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFß signaling, p53 and ß-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.

Telomerase reactivation following telomere dysfunction yields murine prostate tumors with bone metastases.

To determine the role of telomere dysfunction and telomerase reactivation in generating pro-oncogenic genomic events and in carcinoma progression, an inducible telomerase reverse transcriptase (mTert) allele was crossed onto a prostate cancer-prone mouse model null for Pten and p53 tumor suppressors. Constitutive telomerase deficiency and associated telomere dysfunction constrained cancer progression. In contrast, telomerase reactivation in the setting of telomere dysfunction alleviated intratumoral DNA-damage signaling and generated aggressive cancers with rearranged genomes and new tumor biological properties (bone metastases). Comparative oncogenomic analysis revealed numerous recurrent amplifications and deletions of relevance to human prostate cancer. Murine tumors show enrichment of the TGF-ß/SMAD4 network, and genetic validation studies confirmed the cooperative roles of Pten, p53, and Smad4 deficiencies in prostate cancer progression, including skeletal metastases. Thus, telomerase reactivation in tumor cells experiencing telomere dysfunction enables full malignant progression and provides a mechanism for acquisition of cancer-relevant genomic events endowing new tumor biological capabilities.

Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism.

Tumor maintenance relies on continued activity of driver oncogenes, although their rate-limiting role is highly context dependent. Oncogenic Kras mutation is the signature event in pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible Kras(G12D)-driven PDAC mouse model establishes that advanced PDAC remains strictly dependent on Kras(G12D) expression. Transcriptome and metabolomic analyses indicate that Kras(G12D) serves a vital role in controlling tumor metabolism through stimulation of glucose uptake and channeling of glucose intermediates into the hexosamine biosynthesis and pentose phosphate pathways (PPP). These studies also reveal that oncogenic Kras promotes ribose biogenesis. Unlike canonical models, we demonstrate that Kras(G12D) drives glycolysis intermediates into the nonoxidative PPP, thereby decoupling ribose biogenesis from NADP/NADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in PDAC.

A preliminary exploration on the mechanism of the carbapenem-resistance transformation of Serratia marcescens in vivo.

BACKGROUND: The infection of carbapenem-resistant organisms was a huge threat to human health due to their global spread. Dealing with a carbapenem-resistant Serratia marcescens (CRSM) infection poses a significant challenge in clinical settings. This study aims to provide insights into strategies for controlling CRSM infection by exploring the transformation mechanism of carbapenem-resistance. METHODS: We used whole genome sequencing (WGS) to investigate the mechanism of carbapenem resistance in 14 S. marcescens isolates in vivo. The expression level of related genes and the minimum inhibitory concentration of meropenem (MICMEM) were also evaluated to confirm the mechanism of carbapenem resistance. RESULTS: Seven groups of S. marcescens, each consisting of two strains, were collected from a hospital and displayed a shift in MICMEM from low to high levels. Homology analysis revealed that the isolates in five groups were significantly different from the remaining two. WGS and experimental evidence indicated that four groups of strains developed carbapenem resistance by acquiring the blaKPC (obtaining group), while two groups (persisting group) increased the expression level of the blaKPC. In contrast, isolates in the last group (missing group) did not carry the blaKPC. All strains possessed multiple ß-lactamase genes, including blaCTX-M-14, blaSRT-1, and blaSRT-2. However, only in the missing group, the carbapenem-resistant strain lost an outer membrane protein-encoding gene, leading to increased blaCTX-M-14 expression compared to the carbapenem-susceptible strain. CONCLUSION: The study findings suggest that S. marcescens strains developed diverse carbapenem resistance in vivo through the evolution of drug resistance, rather than through clone replacement. We hypothesize that carbapenem resistance in S. marcescens was due to certain clonal types with a distinct mechanism.

Pathogenic germline variants in non-BRCA1/2 homologous recombination genes in ovarian cancer: Analysis of tumor phenotype and survival.

OBJECTIVE: To define molecular features of ovarian cancer (OC) with germline pathogenic variants (PVs) in non-BRCA homologous recombination (HR) genes and analyze survival compared to BRCA1/2 and wildtype (WT) OC. METHODS: We included patients with OC undergoing tumor-normal sequencing (MSK-IMPACT) from 07/01/2015-12/31/2020, including germline assessment of BRCA1/2 and other HR genes ATM, BARD1, BRIP1, FANCA, FANCC, NBN, PALB2, RAD50, RAD51B, RAD51C, and RAD51D. Biallelic inactivation was assessed within tumors. Progression-free (PFS) and overall survival (OS) were calculated from pathologic diagnosis using the Kaplan-Meier method with left truncation. Whole-exome sequencing (WES) was performed in a subset. RESULTS: Of 882 patients with OC, 56 (6.3%) had germline PVs in non-BRCA HR genes; 95 (11%) had BRCA1-associated OC (58 germline, 37 somatic); and 59 (6.7%) had BRCA2-associated OC (40 germline, 19 somatic). High rates of biallelic alterations were observed among germline PVs in BRIP1 (11/13), PALB2 (3/4), RAD51B (3/4), RAD51C (3/4), and RAD51D (8/10). In cases with WES (27/35), there was higher tumor mutational burden (TMB; median 2.5 [1.1-6.0] vs. 1.2 mut/Mb [0.6-2.6]) and enrichment of HR-deficient (HRD) mutational signatures in tumors associated with germline PALB2 and RAD51B/C/D compared with BRIP1 PVs (p < 0.01). Other features of HRD, including telomeric-allelic imbalance (TAI) and large-scale state transitions (LSTs), were similar. Although there was heterogeneity in PFS/OS by gene group, only BRCA1/2-associated OC had improved survival compared to WT OC (p < 0.01). CONCLUSIONS: OCs associated with germline PVs in non-BRCA HR genes represent a heterogenous group, with PALB2 and RAD51B/C/D associated with an HRD phenotype.

Genomic and immunocyte characterisation of bloodstream infection caused by Klebsiella pneumoniae.

OBJECTIVES: The aim of this study was to evaluate the characteristics of immunocyte associated with bloodstream infection (BSI) caused by Klebsiella pneumoniae (Kpn). METHODS: Patients with BSI-Kpn were included from 2015 to 2022 in our hospital. Immunocyte subpopulations of enrolled BSI-Kpn patients were tested on the same day of blood culture using multicolor flow cytometry analysis. Antibiotic susceptibility test was determined by agar dilution or broth dilution method. All included isolates were subjected to whole genome sequencing and comparative genomics analysis. Clinical and genetic data were integrated to investigate the risk factors associated with clinical outcome. RESULTS: There were 173 patients with non-duplicate BSI-Kpn, including 81 carbapenem-resistant Kpn (CRKP), 30 extended-spectrum ß-lactamases producing Kpn (ESBL-Kpn), 62 none CRKP or ESBL-Kpn (S-Kpn). Among 68 ST11-CRKP isolates, ST11-O2v1:KL64 was the most common serotypes cluster (77.9%, 53/68), followed by ST11-OL101: KL47 (13.2%, 9/68). Compared with CSKP group, subpopulations of immunocyte in patients with CRKP were significantly lower (P < 0.01). In patients with ST11-O2v1:KL64 BSI-Kpn, the level of cytotoxic T lymphocytes (CD3 + CD8 +) is the highest, while the B lymphocytes (CD3-CD19 +) was the least. In addition, the level of immunocyte in patients with Kpn co-harbored clpV-ybtQ-qacE were lower than that in patients with Kpn harbored one of clpV, ybtQ or qacE and without these three genes. Furthermore, co-existence of clpV-ybtQ-qacE was independently associated with a higher risk for 30-day mortality. CONCLUSIONS: The results demonstrate that patients with BSI-CRKP, especially for ST11-O2v1:KL64, exhibit lower leukomonocyte counts. In addition, BSI-Kpn co-harbored clpV-ybtQ-qacE is correlated to higher 30-day mortality.

Dynamic cytokine profiles of bloodstream infection caused by Klebsiella pneumoniae in China.

OBJECTIVES: The aim of this work was to assess dynamic cytokine profiles associated with bloodstream infection (BSI) caused by Klebsiella pneumoniae (Kpn) and investigate the clinical features associated with mortality. METHODS: A total of 114 patients with positive BSI-Kpn and 12 sepsis individuals without blood positive bacteria culture were followed up. Cytokine profiles were analyzed by multiplex immunoassay on the first, third, seventh and fourteenth day after diagnosis. The test cytokines included arginase, interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-1ß, IL-4, IL-6, IL-10, IL-12 (p70), and IL-23. The minimum inhibitory concentration (MIC) of 24 antibiotics were tested for BSI-Kpn. Risk factors associated with the 30-day mortality and 120-day mortality were evaluated using logistic analyses and nomogram. RESULTS: There were 55 out of 114 patients with BSI-Kpn were included. All isolates showed high susceptibility rate to novel avibactam combinations. The level of arginase was the highest in carbapenem-resistant Kpn (CRKP) patients. The AUCs of arginase, TNF-α and IL-4 reached 0.726, 0.495, and 0.549, respectively, whereas the AUC for the combination of these three cytokines was 0.805. Notably, 120-day mortality in patients with CRKP was higher than carbapenem-sensitive K. pneumoniae (CSKP). Furthermore, the long-term and high levels of IL-6 and IL-10 were associated with death. CONCLUSIONS: High expression of arginase is correlated with CRKP. In addition, BSI-CRKP could result in indolent clinic course but poor long-term prognosis. Continuous increase of IL-6 and IL-10 were associated with mortality.

Novel SCCmec variants in clonal complex 398 and lineage-specific pseudo-SCCmec identified in ST88 MRSA from invasive bloodstream infections in China.

BACKGROUND: Methicillin resistance in Staphylococcus aureus is primarily due to the mecA gene found in highly diverse staphylococcal cassette chromosome mec (SCCmec) elements, with an increasing number of variants being continually discovered. OBJECTIVES: To characterize two novel SCCmec variants identified in clonal complex (CC) 398 strains and lineage-specific pseudo-SCCmec elements in the ST88 clone. METHODS: WGS and comparative genomic analysis were used to elucidate the SCCmec element diversity of representative isolates. RESULTS: The non-typeable 47 kb SCCmec found in the CC398 strain SKLX55795 represents a novel subtype of XIV, showing significant differences in structural organization and genetic content within the joining regions compared with the XIV element from the prototype strain SC792. This unique subtype comprised remnants from various mobile genetic elements that encode antimicrobial resistance genes, ultimately forming a large MDR region. Genome analysis of CC398 strain SKLX61416 revealed the presence of a novel 50 kb composite SCCmec with two distinct domains, carrying the ccr gene complexes 5/8 and containing genes for the detoxification of arsenic and sulphide. Further sequence analysis disclosed that 44.23% (23/52) of ST88 strains in our collection carried a lineage-specific pseudo-SCCmec, termed ΨSCCmecST88. This ΨSCCmecST88 harboured the mec gene complex C2, along with a series of genes associated with heavy metal resistance, but lacked an approximately 28 kb region encompassing the ccr gene complex. CONCLUSIONS: Our findings provide evidence for the ongoing evolution of SCCmec elements within the CC398 and ST88 clones, underscoring the need for further surveillance to understand the biological significance of these elements.

Antimicrobial use, healthcare-associated infections, and bacterial resistance in general hospitals in China: the first national pilot point prevalence survey report.

The purpose of this study is to implement point prevalence survey (PPS), assess antimicrobial prescribing and resistance in general hospitals and clinical specialties in China, and compare them with similar data from other parts of the world. Twenty general hospitals in China were surveyed in October or November, 2019. A standardized surveillance protocol was used to collect data on patient demographics, diagnosis of infection, the prevalence and intensity of antimicrobial use, prescribing quality, bacterium type and resistance spectrum, and the prevalence and type of healthcare-associated infections (HAIs). Overall, 10,881 beds and 10,209 inpatients were investigated. The overall prevalence of antibiotic use was 37.00%, the use of antibiotic prophylaxis in surgical patients was high (74.97%). The intensity of antimicrobial use was 61.25 DDDs/100 patient days. Only 11.62% of antimicrobial prescriptions recorded the reason for prescribing. Intravenous or combination treatments comprised 92.02% and 38.07%, respectively, and only 30.65% of prescriptions referred to a microbiological or biomarker tests. The incidence of HAIs in all patients was 3.79%. The main associated factors for HAIs included more frequent invasive procedures (27.34%), longer hospital stay (> 1-week stay accounting for 51.47%), and low use of alcohol hand rubs (only 29.79% placed it bedside). Most of the resistant bacteria declined; only carbapenem-resistant Enterobacter is higher than previously reported. The prevalence of antibiotic use in general hospitals fell significantly, the overall bacterial resistance declined, and the incidence of HAI was low. However, the low quality of antimicrobial use requires urgent attention.

Comparison of the inoculum effect of in vitro antibacterial activity of Imipenem/relebactam and Ceftazidime/avibactam against ESBL-, KPC- and AmpC-producing Escherichia coli and Klebsiella pneumoniae.

OBJECTIVE: To evaluate effect of inoculum size of extended-spectrum ß-Lactamase (ESBL)-producing-, AmpC-producing-, and KPC-producing Escherichia coli and Klebsiella pneumoniae on the in vitro antibacterial effects of imipenem/relebactam (IMR) and ceftazidime/avibactam (CZA). METHODS: We compared the impact of inoculum size on IMR and CZA of sixteen clinical isolates and three standard isolates through antimicrobial susceptibility tests, time-kill assays and in vitro PK/PD studies. RESULTS: When inoculum size increased from 105 to 107 CFU/mL, an inoculum effect was observed for 26.3% (5/19) and 52.6% (10/19) of IMR and CZA, respectively; time-kill assays revealed that the concentration of CZA increased from ≥ 4 × MIC to 16 × MIC to reach 99.9% killing rate against K. pneumoniae ATCC-BAA 1705 (KPC-2-, OXA-9- and SHV-182-producing) and 60,700 (SHV-27- and DHA-1-producing). While for IMR, a concentration from 1 × MIC to 4 × MIC killed 99.9% of the four strains. When the inoculum size increased to 109 CFU/mL, neither IMR nor CZA showed a detectable antibacterial effect, even at a high concentration. An in vitro PK/PD study revealed a clear bactericidal effect when IMR administered as 1.25 g q6h when inoculum size increased. CONCLUSION: An inoculum effect on CZA was observed more frequent than that on IMR. Among the ß-lactamase-producing strains, the inoculum effect was most common for SHV-producing and KPC-producing strains.

Comparison of clinical and microbiological characteristics of community-acquired hypervirulent Klebsiella pneumoniae liver abscess in diabetic and non-diabetic patients.

Invasive infection caused by hypervirulent Klebsiella pneumoniae (HvKP) has been reported worldwide. Most of the patients are community population, related to diabetes mellitus (DM), chronic liver disease and other basic diseases, which prone to systemic migratory infection. In this study, we collected 377 patients with community acquired Klebsiella pneumoniae liver abscess in our hospital from January 2013 to December 2018, 65.8% of whom were male, and 49.6% had DM. Patients with DM are prone to eye and central nervous system (CNS) infection, which need continuous local abscess drainage during treatment. Among them, patients with poor blood glucose control have a higher rate of blood stream infections (BSI). 219 strains of HvKP were obtained, with K1/K2 Serotype accounted for 81.7%. The incidence of BSI in K2 patients was higher than that in K1 patients. The PCR results indicate that the carrying rate of virulence genes (rmpA、areo、kfu、allS、iroN、magA、uge、wcaG) in K1/K2 type strains is significantly higher than that in non K1/K2 type strains. ST23 and ST65 are the most common multilocus sequence typing (MLST), which belong to K1 and K2 Serotype respectively. All of HvKP strains showed high sensitivity to commonly used clinical antibiotics other than ampicillin, with 54.3% of the strains exhibiting high viscosity characteristics. Meanwhile, 35 classic Klebsiella pneumoniae (cKP) strains were collected, and their serum typing is mainly non K1/K2. The carrying rate of virulence genes and viscosity degree in HvKP are significantly higher than those in cKP. Primary liver abscess caused by HvKP is prone to multiple tissue and organ infections, but it shows higher sensitivity to most commonly used antibiotics in clinical practice except for ampicillin. After effective treatment, the overall prognosis of patients is better. This study analyzes the pathogenic characteristics of HvKP and elaborates on the clinical characteristics of patients, which can provide reference for clinical and scientific research work.

Molecular epidemiology and change trend of methicillin-resistant Staphylococcus aureus from invasive infections of a hospital in Hangzhou from 2012 to 2018.

The disease caused by methicillin-resistant Staphylococcus aureus (MRSA) is a global public health challenge that threatens society and patients seriously. Therefore, the molecular epidemiology and change trend of MRSA is essential for the control and treatment of diseases caused by the pathogen in their regions. To explore molecular epidemiology of MRSA in Hangzhou, we collected 162 MRSA isolates from 2012 to 2018, conducted the antimicrobial susceptibility and used polymerase chain reaction(PCR) to test the molecular typing including multilocus sequence typing (MLST), staphylococcal chromosome cassette mec (SCCmec), staphylococcal protein A (spa A) and Panton-Valentine leucocidin (PVL). All the strains was divided into community-associated MRSA (CA-MRSA) or hospital-associated MRSA (HA-MRSA). 162 MRSA isolates were divided into 16 STs and 30 spa types. The major ST type was ST5 (96/162, 59.3%) and the predominant spa type was t311 (83/162, 51.2%). Five SCCmec types were found and the most common SCCmec type was type II (101/162, 61.7%). ST5-II-t311 was the predominant MRSA clone. And the prevalence of ST5 MRSA gradually declined from 2014 to 2018 but the prevalence of ST59 MRSA significantly increased. At the same time, livestock-associated methicillin-resistant Staphylococcus aureus(LA-MRSA) ST398 and ST9 were detected. Twenty-eight isolates were PVL gene positive (28/162, 17.3%). The most prevalent PVL-positive clone was ST59-IVa-t437. Comparing with HA-MRSA, CA-MRSA had a lower probability of ST5 (9.1% vs 67.1%, P=0.000) but a higher probability of ST59 (63.6% vs 11.4%, P=0.000), not only that, it was more likely to carrying PVL-positive gene (36.4% vs 14.3%, P=0.028). In summary, the molecular types of MRSA were getting complex over time. ST5-II-t311 was the predominant clone of MRSA isolate with a downward incidence from 2014 to 2018. ST59 MRSA strains, which is thought community related strain are spreading into hospitals and has an upward incidence from 2014 to 2018.

A Multifluorination Strategy Toward Wide Bandgap Polymers for Highly Efficient Organic Solar Cells.

Creating new electron-deficient unit is highly demanded to develop high-performance polymer donors for non-fullerene organic solar cells (OSCs). Herein, we reported a multifluorinated unit 4,5,6,7-tetrafluoronaphtho[2,1-b : 3,4-b']dithio-phene (FNT) and its polymers PFNT-F and PFNT-Cl. The advantages of multifluorination: (1) it enables the polymers to exhibit low-lying HOMO (≈-5.5 eV) and wide band gap (≈2.0 eV); (2) the short interactions (F⋅⋅⋅H, F⋅⋅⋅F) endow the polymers with properties of high film crystallinity and efficient hole transport; (3) well miscibility with NFAs that leads to a more well-defined nanofibrous morphology and face-on orientation in the blend films. Therefore, the PFNT-F/Cl : N3 based OSCs exhibit impressive FF values of 0.80, and remarkable PCEs of 17.53 % and 18.10 %, which make them ranked the best donor materials in OSCs. This work offers new insights into the rational design of high-performance polymers by multifluorination strategy.

Utility and Applicability of Rapid Diagnostic Testing in Antimicrobial Stewardship in the Asia-Pacific Region: A Delphi Consensus.

Rapid diagnostic tests (RDTs) facilitate fast and accurate identification of infectious disease microorganisms and are a valuable component of multimodal antimicrobial stewardship (AMS) programs but are currently underutilized in the Asia-Pacific region. An experienced group of infectious diseases clinicians, clinical microbiologists, and a clinical pharmacist used a modified Delphi consensus approach to construct 10 statements, aiming to optimize the utility and applicability of infection-related RDTs for AMS in the Asia-Pacific region. They provide guidance on definition, types, optimal deployment, measuring effectiveness, and overcoming key challenges. The Grading of Recommendations Assessment, Development, and Evaluation system was applied to indicate the strength of the recommendation and the quality of the underlying evidence. Given the diversity of the Asia-Pacific region, the trajectory of RDT development will vary widely; the collection of local data should be prioritized to allow realization and optimization of the full benefits of RDTs in AMS.

Facile Solution-Refluxing Synthesis and Photocatalytic Dye Degradation of a Dynamic Covalent Organic Framework.

Covalent organic frameworks (COFs), as a novel crystalline porous adsorbent, have been attracting significant attention for their synthesis and application exploration due to the advantages of designability, stability, and functionalization. Herein, through increasing the concentration of the acid catalyst, a facile solution-refluxing synthesis method was developed for the preparation of a three-dimensional dynamic COF material, COF-300, with high yields (>90%) and high space−time yields (>28 kg m−3 day−1). This synthesis method not only permits gram-scale synthesis, but also yields products that well maintain porosity and unique guest-dependent dynamic behavior. Moreover, the catalytic activity of COF-300 as a metal-free photocatalyst was explored for the first time. Under 365 nm ultra-violet light irradiation, COF-300 can effectively catalyze the dye degradation (>99%) in wastewater with good recyclability. By adding magnetic Fe3O4 nanoparticles into the solution-refluxing synthesis of COF-300, Fe3O4/COF-300 nanocomposites can be obtained and used as magnetically recyclable photocatalysts, demonstrating the superiority of this facile synthesis procedure. Our study provides new insights for the preparation of COF materials and a constructive exploration for their water treatment application.

Lateral monolayer MoS2 homojunction devices prepared by nitrogen plasma doping.

Monolayer MoS2 possesses good electron mobility, structural flexibility and a direct band gap, enabling it to be a promising candidate for flexible and wearable optoelectronic devices. In this article, the lateral monolayer MoS2 homojunctions were prepared by a nitrogen plasma selective doping technique. The monolayer MoS2 thin films were synthesized by chemical vapor deposition and characterized by photoluminescence, atom force microscope and Raman spectroscopy. The electronic and photoelectric properties of the lateral pn and npn homojunctions were discussed. The results showed that the rectifying ratio of the pn homojunction diode is ∼103. As a photodetector of pn homojunction, the optical responsivity is up to 48.5 A W-1, the external quantum efficiency is 11 301%, the detectivity is ∼109 Jones and the response time is 20 ms with the laser of 532 nm and the reverse bias voltage of 10 V. As a bipolar junction transistor of npn homojunction, the amplification coefficient reached ∼102. A controllable plasma doping technique, compatible with traditional CMOS process, is utilized to realize the monolayer MoS2 based pn and npn homojunctions, and it propels the potential applications of 2D materials in the electronic, optoelectronic devices and circuits.

Optimal empiric treatment for KPC-2-producing Klebsiella pneumoniae infections in critically ill patients with normal or decreased renal function using Monte Carlo simulation.

BACKGROUND: Limited clinical studies describe the pharmacodynamics of fosfomycin (FOS), tigecycline (TGC) and colistin methanesulfonate (CMS) in combination against KPC-producing Klebsiella pneumoniae (KPC-Kp). Population pharmacokinetic models were used in our study. Monte Carlo simulation was conducted to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR) of each agent alone and in combination against KPC-Kp in patients with normal or decreased renal function. RESULTS: The simulated regimen of FOS 6 g q8h reached ≥90% PTA against a MIC of 64 mg/L in patients with normal renal function. For patients with renal impairment, FOS 4 g q8h could provide sufficient antimicrobial coverage against a MIC of 128 mg/L. And increasing the daily dose could result to the cut-off value to 256 mg/L in decreased renal function. For TGC, conventional dosing regimens failed to reach 90% PTA against a MIC of 2 mg/L. Higher loading and daily doses (TGC 200/400 mg loading doses followed by 100 mg q12h/200 mg q24h) were needed. For CMS, none achieved 90% PTA against a MIC of 2 mg/L in normal renal function. Against KPC-Kp, the regimens of 200/400 mg loading dose followed by 100 q12h /200 mg q24h achieved > 80% CFRs regardless of renal function, followed by CMS 9 million IU loading dose followed by 4.5/3 million IU q12h in combination with FOS 8 g q8h (CFR 75-91%). CONCLUSIONS: The use of a loading dose and high daily dose of TGC and CMS in combination with FOS can provide sufficient antimicrobial coverage against critically ill patients infected with KPC-Kp.

Change in Antibiotic Use in Secondary and Tertiary Hospitals Nationwide After a National Antimicrobial Stewardship Campaign Was Launched in China, 2011-2016: An Observational Study.

BACKGROUND: An antimicrobial stewardship campaign was launched in 2011 by the Ministry of Health. This study aimed to assess the achievements and trends in the clinical use of antibiotics in secondary and tertiary hospitals following this campaign in China. METHODS: This observational study analyzed nationwide hospital antibiotic procurement and consumption data and antibiotic-resistance surveillance data based on claims filed in 2010-2016. RESULTS: After a 6-year national campaign, the proportion of outpatients and surgical patients who received antibiotic treatment decreased from 19.5% to 8.5% and from 97.9% to 38.3%, respectively. The intensity of antibiotic use among inpatients decreased from 85.3±29.8 defined daily dosage (DDD) per 100 patient days to 48.5±8.0 DDD per 100 patient days. Moreover, the antibiotic procurement expenditure among hospitals declined from 22.3% of total drug procurement costs in 2010 to 12.1% in 2016, although total drug procurement costs doubled during that time. The incidence of methicillin-resistant Staphylococcus aureus isolates also dropped (from 54.4% in 2010 to 34.4% in 2016), as did the proportion of carbapenem-resistant Pseudomonas aeruginosa isolates (from 30.8% to 22.3%). CONCLUSIONS: The 6-year campaign successfully reduced antibiotic consumption and irrational drug use in Chinese hospitals which was associated with declines in the prevalence of common antibiotic-resistant bacteria.

A Retrospective Analysis of Risk Factors and Outcomes of Carbapenem-Resistant Klebsiella pneumoniae Bacteremia in Nontransplant Patients.

BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae (CRKP) has become a major problem among nosocomial infections, and it is a serious threat to patients. The clinical characteristics and outcome of CRKP bloodstream infection (BSI) in nontransplant patients remains unelucidated. The aim of this study was as follows: identify the risk factors of CRKP infection; generate new ideas for prevention; and generate new ideas for the most effective therapeutic management in nontransplant patients. METHODS: The study retrospectively analyzed the clinical and microbiological data of nontransplant patients with K pneumoniae (KP) bacteremia from January 2013 to December 2015 to identify risk factors, clinical features, and outcomes using multivariate logistic regression analysis. RESULTS: Of the 371 patients with KP-BSI in nontransplant patients included in this study, 28.0% (N = 104) had CRKP. The 28-day mortality was higher in patients infected with CRKP (55.8%) than in those with carbapenem-susceptible KP (13.9%) (P < .001). Multivariate analysis showed previous gastric catheterization, previous use of carbapenems, hypoproteinemia, and high Acute Physiologic Assessment and Chronic Health Evaluation II scores as independent risk factors for CRKP-BSIs. Carbapenem-resistant KP infection, severe illness, and tigecycline therapy were independent risk factors for death from KP-BSIs. Taken together, inappropriate antibiotic treatment both in empirical and definitive therapy and imipenem minimum inhibitory concentrations (MICs) of >8 mg/L were associated with poor clinical outcome. CONCLUSIONS: Nontransplant patients with CRKP-BSI had higher mortality. Carbapenems exposure was an independent risk factor for CRKP infection. Imipenem MICs of >8 mg/L, tigecycline therapy, and inappropriate treatments increased the 28-day mortality of KP-BSI patients.

Harnessing Shape Complementarity for Upgraded Cyclohexane Purification through Adaptive Bottlenecked Pores in an Imidazole-Containing MOF.

Shape complementarity is a biological craft for precisely binding substrates at protein-protein interfaces. An analogy to such a function can be drawn conceptually for crystalline porous solids; yet the manifested entities are rare in reticular chemistry. The bottleneck-shaped pores carved out of a metal-organic framework, Zn(MIBA)2 (aka. MAF-stu-13), can perfectly accommodate benzene molecules. Remarkably, its framework adapts to the optimal guest binding-the enhanced host-guest interactions in the neck in turn minimize the guest-guest repulsion in the pore to the extent it turns into attraction-as demonstrated by the combined X-ray structural and DFT computational studies. This adaptive material can be used for liquid-phase production of ultrahigh-purity (≥99 %) cyclohexane, achieving a balance between uptake capacity and separation selectivity and surpassing the performances of other porous and nonporous crystals reported recently (e.g. product purity 99.4 % vs. 97.5 % to date).